The composition of the invention is individually coated granules adapted for oral administration as such, i.e. the composition is a "granulate" composition ready for use. The granule composition of the invention is an advantageous administration form in many clinical situations, e.g. with respect to patient having difficulties in swallowing and with respect to children not wanting to swallow tablets.
A further advantage is that the granules or the invention may be packaged in unit dosage forms comprising larger amounts of active 5-ASA, e.g. in sachets or sticks.
In principle, there is, in contrast to the maximal content of tablets and capsules, no upper limit to the amount of active ingredients in a unit dosage form of the composition according to the invention.
Thus, an advantage of the granule composition of the present invention is that it enables improved compliance values with respect to the therapy regimen, a clinically important parameter for the treatment of chronic diseases.
Overall, it should be noted that the question of a satisfactory compliance is especially important in the case of IBD, since failure to respond to medical treatment in many cases necessitates surgery, with the standard surgical operation in the treatment of ulcerative colitis in many cases being total proctocolectomy (removal of the colon and the rectum).
U.S. Pat. Nos. 4,496,553 and 4,980,173 (lIalskov) provide a method for the treatment of IBD by oral administration of 5-ASA compositions consisting essentially of free 5-ASA and carriers which will control the release of an effective amount of 5-ASA.
However, as opposed to the present invention, no mention of the administration of 5-ASA granules as such was disclosed, and the compositions described for clinical use were all in the form of tablets. The disclosure of said U.S. patents, including the examples, is totally silent about the provision of a specific type of granule composition for direct oral intake. Nowhere in said patent specification is it suggested to develop or administer a granule composition.
Thus, in the examples of the above U.S. patents, preparations of granulates pressed to form tablets with a diameter of 13.5 mm and a weight of 650 mg/tablet containing 250 mg of 5-AsA. The resulting tablets were used in clinical tests.
In the examples of the U.S. patents, two intermediary preparations of granulates were described, one of them comprising 5-ASA, and the other being a "helper" granulate without 5-ASA, said "helper" granulate being prepared and admixed in order to facilitate the tablet compression involving the addition of talc and a lubricant mixture.
The 173 patent more specifically claims a method for the preparation of sustained-release tablets, useful for the treatment of colitis ulcerosa or Crohn's disease, comprising the steps of
a) preparing a first granulate from 5-ASA or a pharmaceutically acceptable salt or ester thereof and bout 10% by weight (solids content based on the 5-ASA) of polyvinylpyrrolidone in an organic solvent thereby to provide granules of a particle size from about 0.7 to 1 mm, upon evaporation of the solvent. PA1 b) applying onto said granules a coating composition, comprising a solution in an organic solvent of a pharmaceutically acceptable coating material which will gradually release the active ingredient upon arrival at the small intestine, thereby to provide coated granules upon evaporation of the solvent, PA1 c) mixing the first granulate with about 5% by weight, calculated on the total solids content, of a lubricant and a conventional pharmaceutical tablet carrier in an amount in accordance with the desired size and active ingredient content of the tablet, and PA1 d) forming tablets from the resulting mixture PA1 an oral modified release composition ensuring bioavailability of said 5-ASA in both the small and large intestine, and comprising: PA1 the majority of the granules, preferably more than 80%, more preferably more than 90%, of the granules being essentially spherical as defined by an aspect ratio within 1.00-1.25, preferably within 1.00-1.20, more preferably within 1.00-1.15; and PA1 the majority of the granules, preferably more than 70%, more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0.5 mm-2.0 mm, preferably in the range of 0.7 mm-1.1 mm; and PA1 the composition exerting the following in vitro dissolution rates [when measured in a model system using simulated intestinal fluid in USP Paddle System 2 operated at 37.degree. C. with stirring speed 100 rpm]: PA1 straight chain or branched C.sub.1 -C.sub.18 alkyl esters, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl, etc., PA1 straight chain or branched C.sub.2 -C.sub.18 alkenyl esters, e.g. vinyl, allyl, undecenyl, oleyl, linolenyl, etc., PA1 C.sub.3 -C.sub.8 cycloalkyl esters, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, etc., PA1 aryl esters, e.g. phenyl, toluyl, xylyl, naphthyl, etc., PA1 alicyclic esters, e.g. menthyl, etc., or PA1 aralkyl esters, e.g. benzyl, phenethyl, etc. PA1 individually coated granules, each granule comprising: PA1 the majority of the granules, preferably more than 80%, more preferably more than 90%, of the granules being essentially spherical as defined by an aspect ratio within 1.0-1.25, preferably within 1.00-1.20, more preferably within 1.00-1.15; and PA1 the majority of the granules, preferably more than 70%, more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0.5 mm-2.0 mm, preferably in the range of 0.7 mm-1.1 mm; and PA1 the composition exerting the following in vitro dissolution rates [when measured in a model system using simulated intestinal fluid in USP Paddle System 2 operated at 37.degree. C. with stirring speed 100 rpm]: PA1 provided the gastric emptying is within the normal range, 50% of the granules have left the stomach within 60 minutes after intake of the composition, preferably within 30 minutes. PA1 provided the small bowel transit time is within the normal range, 50% of the granules is present in the small bowel 3-6 hours after intake of the composition. PA1 provided the large bowel transit time is within the normal range, 50% of the granules is present in the large bowel 12-50 hours after intake of the composition. PA1 the majority of the granules, preferably more than 80%, more preferably more than 90%, of the granules are essentially spherical as defined by an aspect ratio within 1.00-1.25, preferably within 1.00-1.20, more preferably within 1.00-1.15. PA1 1.40 mm-1.25 mm-1.12 mm-1.00 mm-0.710 mm-0.50 mm-0.355 mm-0.250 mm. PA1 the majority of the granules, preferably more than 70%, more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0.5 mm-2.0 mm, preferably in the range of 0.7 mm-1.1 mm. PA1 a) within 2-20%, preferably within 5-15%, of the total 5-ASA is released after 15 minutes in the model system; PA1 b) within 20-50%, preferably within 25-45% of the total 5-ASA is released after 60 minutes in the model system; PA1 c) within 30-70%, preferably within 40-60% of the total 5-ASA is released after 90 minutes in the model system; PA1 d) within 50-90%, preferably within 55-80%, of the total 5-ASA is released after 150 minutes in the model system; PA1 e) within 75-100% of the total 5-ASA is released after 240 minutes in the model system. PA1 the majority of the granules, preferably mote than 80%, more preferably more than 90%, of the granules being essentially spherical as defined by an aspect ratio within 1.00-1.25, preferably within 1.00-1.20, more preferably within 1.00-1.15; and PA1 the majority of the granules, preferably more than 70% , more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0.5 mm-2.0 mm, preferably in the range of 0.7 mm-1.1 mm. PA1 Minimum=0.751 mm-maximum=1.101 mm, PA1 i.e. the range was from 0.75 to 1.10 mm. PA1 Minimum=0.674 mm-maximum=0.920 mm, PA1 i.e. the range was from 0.67 to 0.92 mm. PA1 Minimum=1.029-maximum=1.250 PA1 i.e. the range of aspects ratios was from 1.03 to 1.25. PA1 Minimum=0.712mm-maximum=1.010 mm, PA1 i.e. the range was from 0.71 to 1.01 mm. PA1 Minimum=0.648 mm-maximum=0.907 mm, PA1 i.e. the range wag from 0.65 to 0.91 mm. PA1 Minimum=1.016-maximum=1.266 PA1 i.e, the range of aspects ratios was from 1.02 to 1.27.
Preferably the coating material is a cellulose derivative.
The specific requirements to the 5-ASA release properties of the granule composition as identified by the present inventors and defined by the present invention, were nowhere described or suggested in said U.S. patents, let alone any hint or guidance as to how to arrive at the specific embodiments of the invention, said embodiments solving the problems identified and thus providing advantages in a non-predictable way.